Salts of L-ornithine are valuable pharmaceutical products. They are useful, e.g., for parenteral nutrition (L-ornithine acetate or L-ornithine monohydrochloride) and the treatment of hepatic diseases (L-ornithine aspartate or L-ornithine-2-ketoglutarate). L-ornithine can replace L-arginine, an amino acid which is essential in infants and children, in all functions. A deficiency of arginine or ornithine can result in damage up to death, e.g. by means of a super-elevated ammonia level after the take-up of amino acid after a period of fasting or of malnourishment (so-called protein shock). L-ornithine therefore has considerable commercial potential.
L-arginase is an enzyme which catalyses the hydrolysis of L-arginine to L-ornithine and urea in the urea cycle of higher mammals. It can be isolated from the livers of various higher mammals such as the cow, calf or rat and was primarily used in the past for diagnostic purposes.
As is known, L-arginase exhibits a narrow substrate spectrum, so that, in addition to L-arginine, only few analogues are converted. However, almost all research concentrated in the past on levorotary (L-) compounds. L-arginine is obtained today almost exclusively from biological sources such as fermentation or protein hydrolyzates. No D-arginine forms in these two methods. Only a little testing has been performed on D-arginine as a substrate, with varying results (D. Kavanaugh, M. A. Berge and G. A. Rosenthal, Plant Physiol. 1990, 94, 67-70; G. Muszynska, L. O. Severina and L. V. Lobyreva, Acta Biochim. Pol. 1972, 19, 109-116). DL-arginine, accessible by means of the chemical racemization of L-arginine, has not yet been investigated as a potential substrate of L-arginase, that is, the enantioselectivity of arginase was previously unknown. It also was not known in the past whether D-arginine exerts an inhibitory action on arginase.
D-arginine also is a useful product in its own right. Thus, there is an increasing demand for synthetic D-Arginine for use in the manufacture of pharmaceutical peptides such as LHRH antagonists. Like many D-amino acids, it is not so readily attacked by enzymes in the body as the natural analogues.
L-ornithine is advantageously obtained from L-arginine in industry by the same reaction as in the body of mammals. During the enzymatic process, L-arginase (L-arginine amidino hydrolase, E.C. 3.5.3.1.) from mammal livers is used. In addition to the enzymatic method, the fermentation from glucose by means of the strains Brevibacterium, Corynebacterium and Arthrobacter, as well as the chemical hydrolysis of L-arginine can be used as synthetic methods for producing L-ornithine and its salts.
The enzymatic process has distinct advantages over the alternatives:
The market is too small for the fermentative route; PA1 The chemical hydrolysis of L-arginine results in side reactions, e.g. racemization or deiminization to citrulline.
A disadvantage of the enzymatic process consisted until recently in the limited availability of arginase since the enzyme was used only in diagnostics. However, several firms have been offering the enzyme for a few years now, in some instances in the raw form.